Page 1 of 63 Diabetes

Brief Report

Loss of B cell anergy in type 1 diabetes is associated with high risk HLA and non- HLA disease susceptibility alleles

Mia J. Smith1,2, Marynette Rihanek3, Clive Wasserfall4, Clayton E. Mathews4, Mark A. Atkinson4,5, Peter A. Gottlieb3, and John C. Cambier1

1Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO; 2Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO; 3Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO; 4Department of Pathology, Immunology, and Laboratory Medicine, The University of Florida College of Medicine, Gainesville, FL; 5Department of Pediatrics, The University of Florida College of Medicine, Gainesville, FL

Corresponding Author: John C. Cambier 12800 E 19th Avenue RC1 North, P188100 Aurora, CO 800452537 Phone: 3037248663 Email: [email protected]

Condensed Title: Genetic associations with loss of B cell anergy in type 1 diabetes Word Count: 2557/2000, Abstract (202/200), Figures (3), Tables (0), References (37/25)

Diabetes Publish Ahead of Print, published online January 17, 2018 Diabetes Page 2 of 63

Although B cells reactive with islet autoantigens are silenced by tolerance

mechanisms in healthy individuals, they can become activated and contribute to

development of type 1 diabetes. We previously demonstrated that high-affinity

insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment

in peripheral blood of healthy subjects. Consistent with their activation early in

disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all autoantibody positive pre- diabetic and new-onset type 1 diabetes patients, a time when they are found in pancreatic islets. Loss of BND IBCs is associated with loss of the entire BND B cell

compartment, consistent with provocation by an environmental trigger or

predisposing genetic factors. To investigate potential mechanisms operative in

subversion of B cell tolerance, we explored associations between HLA and non-

HLA type 1 diabetes-associated risk allele genotypes and loss of BNDs in FDRs.

We found that high-risk HLA alleles and a subset of non-HLA risk alleles, i.e.

PTPN2 (rs1893217), INS (rs689) and IKZF3 (rs2872507), relevant to B and T cell

development and function, are associated with loss of anergy. Hence, our results

suggest a role for risk-conferring alleles in perturbation of B cell anergy during

development of type 1 diabetes.

Page 3 of 63 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease in which selfreactive lymphocytes

destroy insulinproducing pancreatic beta cells. While genetic variation is thought to be

the major contributor to risk of developing T1D, environment also plays a contributing

role. Together, these factors may impart their effects by compromising maintenance of

immune tolerance in T cells and/or B cells, both of which are known to be essential in

the pathogenesis of the disorder (14). Studies have shown that B cells likely act as

antigen presenting cells and autoantibody producers in type 1 diabetes (5; 6). How self

reactive B cells, which are normally silenced in healthy individuals, become activated to

participate in this disease is not known.

Previous studies have demonstrated that up to 70% of all B cells generated in

the bone marrow are autoreactive (7). Autoreactive B cells are silenced by multiple

mechanisms. Those reactive with highly avid selfantigens, e.g. cell surface proteins,

undergo receptor editing, in which they rearrange their antigen receptor light chains

modifying specificity (8). If this process fails to eliminate autoreactivity, cells can

undergo apoptosis via a mechanism referred to as clonal deletion (9). Cells reactive

with low avidity autoantigens, even if they have high affinity, do not receive signals that

are sufficiently strong to induce receptor editing or clonal deletion. These cells mature

and proceed to the periphery where they are maintained in a state of unresponsiveness

termed anergy. Anergic B cells show evidence of previous antigen exposure including

downregulation of surface IgM, elevated basal calcium and activation of negatively

regulating signaling circuitry, but are refractory to further stimulation (1012).

Importantly, studies in mice have demonstrated that anergy is rapidly reversed if

autoantigen dissociates from the B cell receptor (BCR), suggesting that this Diabetes Page 4 of 63

unresponsive state is maintained by a nondurable, presumably fragile, biochemical mechanism, rather than genetic reprogramming (13). Consistent with this mechanism, inhibitory signaling pathways are upregulated in anergic cells by protein phosphorylation, e.g. SHIP1 and SHP1, and miRNA regulation of effector expression, e.g. PTEN (14; 15). B cell intrinsic expression of these regulatory phosphatases is required for maintenance of anergy (14). It is likely that additional genetic factors play a role in tuning B cell responsiveness to antigen and maintenance of anergy. Obvious candidates reside among the products of gene alleles that have been shown to confer increased risk of developing autoimmunity.

We previously examined the status of insulinreactive B cells (IBC) in peripheral blood of healthy individuals. We observed that B cells with highaffinity for insulin occur in blood of healthy subjects where they are restricted in the anergic compartment (16).

These cells are polyreactive, binding to LPS and chromatin, as well as insulin.

Interestingly, they disappear from this compartment in islet autoantibodypositive and recentonset type 1 diabetes subjects, as well as a portion of healthy firstdegree relatives (FDRs) of type 1 diabetes patients (Figure 1 and Supplemental figure 1).

Preliminary studies in our lab suggest the disappearance of these cells reflects their relocalization to the pancreas and pancreatic lymph nodes. Specifically, IBC are enriched among B cells in pancreatic islets of type 1 diabetics (Smith and Cambier, unpublished). However, we cannot rule out the possibilities that these cells simply upregulate surface IgM, and thus enter the mature naïve compartment, or do not enter the anergic compartment. Page 5 of 63 Diabetes

To better understand what factors contribute to loss of B cells from the anergic

compartment of blood early in type 1 diabetes, we explored the correlation between BND

frequency among FDRs and highrisk HLA and nonHLA type 1 risk allele genotype. Diabetes Page 6 of 63

RESEARCH DESIGN AND METHODS

Subject selection and peripheral blood processing

Peripheral blood was obtained with informed consent at the Barbara Davis Center for

Childhood Diabetes using protocols approved by the University of Colorado Institutional

Review Board. Eligible type 1 diabetes subjects were males or females who met the

American Diabetes Association criteria for classification of disease. Autoantibodies

against insulin (IAA), GAD, IA2, and ZnT8 were assayed using radioimmunoassays, as

previously described (17). Peripheral blood mononuclear cells (PBMCs) from

autoantibody negative FDR (n=103), autoantibody positive prediabetes subjects (n=18;

identified in the Type 1 Diabetes TrialNet Natural History study), newonset type 1

diabetes patients (n=21; duration < 12 months), longstanding type 1 diabetes patients

(n=21; duration > 12 months), and healthy age/sex matched controls (n=49) were

isolated from heparinized blood by FicollHypaque fractionation. DNA was extracted

from the granulocyte layer using the DNA midi kit (Qiagen).

Flow cytometric analysis and enrichment of IBCs

In order to maintain consistency of gating of flow cytometry data, each subject sample

set was analyzed in parallel with an age/sex matched healthy control. The healthy

control cells were used to construct gates, which were then copied to the FDR subject

cells. Gating for BND cells was based on CD19 T cells and FMO compensation controls.

PBMCs were stained in PBS/1%BSA/0.02%NaAzide with human FcR Blocking Reagent

(Miltenyi), 0.1 g/106 cells insulinbiotin, and mouse monoclonal antihuman antibodies

against CD19BV510 (BioLegend), CD27PerCP or CD27BUV395 (BioLegend), IgM Page 7 of 63 Diabetes

PE (Southern Biotech), and IgDFITC (BD Biosciences) or IgDBV421 (BioLegend) for

20 minutes at 4ºC. After washing, cells were fixed with 2% formaldehyde at 4ºC,

followed by incubation with streptavidinAlexaFlour647 for 20 minutes at 4ºC. Cells were

washed, suspended in MACS buffer (PBS/0.5%BSA/2mMEDTA), and incubated with

AntiCy5/AntiAlexa647 microbeads (Miltenyi) for 15 minutes at 4ºC. Samples were then

passed over magnetized LS columns (Miltenyi), washed 3 times with 2 mL of MACS

buffer, and bound cells were eluted with 6 mL of MACS buffer. Flow cytometry was

preformed an LSR II (BD) and data analyzed with FlowJo software version 8.8.4.

Absolute cell counts were performed using a hemocytometer (Fischer Scientific) to

enumerate total lymphocytes. Total B cell numbers were then determined by multiplying

the frequency of CD19+ B cells determined by FACS by the total cell count determined

by the hemocytometer. Absolute IBC numbers were determined by multiplying the

frequency of IBCs in the CD19+ B cell gate by the total B cell count. Absolute IBC BND

cells were determined by multiplying the frequency of CD27 IgMlo/ IgD+ cells within the

IBC gate by the total IBC cell count.

HLA and non-HLA genotyping

DNA from FDRs (n=103) and healthy controls (n=49) was HLA genotyped at the

Autoantibody/HLA Service Center at the Barbara Davis Center for Childhood Diabetes

using established protocols (18). DNA from 60 FDRs was sent to the University of

Florida Center for Pharmacogenomics for nonHLA genotyping. The purified DNA was

then genotyped on a custom Taqman single nucleotide polymorphism (SNP) genotyping Diabetes Page 8 of 63

array (ThermoFisher). All results from nonHLA genotyping are available in

Supplemental Table 1.

Statistics

Data were analyzed using Prism software (GraphPad Software, Inc.). Oneway ANOVA followed by a Bonferroni’s Multiple Comparison posttest was used to determine significance of differences along the five patient groups, defined as P<0.05. Mann

Whitney nonparametric unpaired t tests were used to determine differences in nonHLA

genetic risk alleles. Page 9 of 63 Diabetes

RESULTS

As previously described and depicted in Figure 1A, we used magnetic nanoparticles to

enrich IBCs from the peripheral blood of healthy individuals and subjects along a

continuum of diabetes development (16; 19), including FDRs (n=103), autoantibody

positive (n=18), recentonset (< 12 months) type 1 diabetes (n=21), long standing (>1

year) type 1 diabetes (n=21), and healthy controls (n=49). We conducted phenotypic

analysis of IBCs to determine what proportion fell into the BND population (Figure 1B).

Phenotypically BND cells appear as mature naïve B cells but have downregulated

surface IgM but retained IgD. We have previously reported that IBCs in the BND

population have a very high affinity (~6.6 x 1010 mol/L) for insulin, but are refractory to

stimulation through BCR based on decreased calcium flux and phosphorylation of Syk

(16).

While the absolute number (Supplemental figure 1) and frequency of total B cells

and IBCs did not vary significantly among subject groups, we found that the anergic

IBCs were absent, both in frequency and cell number, in blood in all autoantibody

positive and recentonset type 1 diabetes subjects compared to longstanding and

healthy controls (Figure 1C, Supplemental figure 1). The observed loss of IBC BND cells

from peripheral blood without a change in total IBC numbers is likely due to the very low

frequency of anergic cells within this population and variability in the number of total B

cells among individuals. As previously shown, FDRs display heterogeneity in BND

phenotype. We hypothesized that BNDlow individuals may be at increased risk for

development of autoantibodies and eventually, type 1 diabetes. In order to first rule out

the possibility that loss of BND is simply a function of young age, we analyzed the Diabetes Page 10 of 63

frequency of BND cells in FDRs in various age groups. As seen in Figure 1D, there were no significant ageassociated differences in BND frequency.

In order to understand what drives loss of IBC BND cells from peripheral blood

and determine whether the low IBC BND phenotype of FDRs is associated with specific type 1 diabetes risk alleles, we HLA genotyped FDRs. Interestingly, FDRs who carried the high risk HLADR3/4DQ2/8 and HLADR4/4DQ8/8 haplotypes uniformly had very low IBC BND cell frequency in blood, while subjects heterozygous for the moderate risk

HLADR4DQ8 and HLADR3DQ2 genotypes showed similar levels as subjects

carrying nontype 1 diabetes riskassociated HLA haplotypes (Figure 2A). Surprisingly,

FDRs who carried the type 1 diabetes protective HLADQB1*0602 (DQ6) allele (20) had

a significantly elevated frequency of IBC BND cells in blood, suggesting enhanced

tolerance of autoreactive cells in these individuals. Particularly, if highrisk type 1

diabetes HLA genotypes function in isolation, i.e. not influenced by other riskconferring

alleles or environmental factors, to regulate IBC levels, the effect of these genes might

be seen in healthy control subjects. Though none of the controls we genotyped carried

the highrisk HLADR3/4DQ2/8 genotype, we saw a significant decrease in IBC BND

frequency in carriers of the HLADR4/4DQ8/8 genotype associated with highrisk for

type 1 diabetes and significant increase in IBC BND in carriers the protective HLADQ6

allele (Figure 2B).

Finally, we explored whether nonHLA type 1 diabetes susceptibility risk

conferring alleles affect maintenance of B cell anergy. We used an Immunochip to

assay over 50 nonHLA riskassociated SNPs. In order to best detect the effect of each

allele, we analyzed only FDRs that were heterozygous for the HLADR3DQ2 or non Page 11 of 63 Diabetes

type 1 diabetes associated HLA alleles (n=60) because these individuals were most

heterogeneous in BND frequency. We reasoned that the impact of nonHLA risk alleles

might be evident in this population. These studies indicated that loss of IBC BND cells is

associated with polymorphisms in the INS (rs689), PTNP2 (rs1893217), and IKZF3

(rs2872507) genes. In addition, reduced IBC BND frequency was observed in carriers of

the high risk PTPN22 (rs2476601) SNP, though significance was not reached due to the

low frequency of this allele in the subject group (Figure 3).

Diabetes Page 12 of 63

DISCUSSION

Previous studies have shown that HLA class II is the major determinant of risk for type 1 diabetes development (21). While both the HLADR4DQ8 and HLADR3DQ2 haplotypes confer the highest risk (22), development of insulin autoantibodies (IAAs) is more frequent among subjects with HLADR4DQ8 (23; 24). Investigations have also demonstrated that the HLADQ8 molecule has an amino acid substitution at position 57 in the P9 pocket of the binding groove that creates a wider peptidebinding groove (25;

26). Some argue this substitution allows promiscuous binding and presentation of peptides, including those of insulin (26). Hence, it is interesting that decreased frequency of anergic insulinreactive B cells is closely associated with the DR4DQ8 haplotype in FDRs. It is tempting to speculate that CD4+ T cells recognizing insulin peptides presented by IBCs may promote loss of anergy. However, it is also important to note that in a parallel study we found that unlike ex vivo IBC from NOD mice, anergic

IBC from C57BL/6.H2g7 do not process and display insulin 923 peptide in association with MHC II (Smith and Cambier, submitted). Thus, we hypothesize a twostep process in which B cells first lose anergy, gaining the ability to signal through BCR and to process and present antigen, and are then further stimulated by T cells. These activated cells accumulate in pancreatic islets as shown by Leete et al. (27).

Consistent with the possibility that T cells promote departure of IBC from the BND compartment is association with SNP rs689 located in the highest riskconferring non

HLA region, INS. It is thought that carriers of this risk allele have decreased expression of insulin peptides in the thymus, leading to decreased negative selection of insulin reactive T cells (28). In addition, a recent study found the rs689 polymorphism is Page 13 of 63 Diabetes

significantly associated with development of IAAs, but not other autoantibodies, in type

1 diabetes patients (29). Hence, it seems plausible that carriers of this polymorphism

have increased numbers of peripheral insulinreactive T cells that, because they

escaped central tolerance, could promote loss or prevent establishment of B cell anergy

by providing the necessary T cell help to an insulinreactive B cell.

Departure of IBC from the BND compartment is also associated with the PTPN2

SNP rs1893217. PTPN2 is broadly expressed in both B and T cells as well as in

pancreatic beta cells. Studies have shown PTPN2 has a range of functions, including

negative regulation of JAK/STAT signaling (30) and dephosphorylation of Lck and Fyn

after stimulation through the T cell antigen receptor (31). In addition, the type 1 diabetes

susceptibility PTPN2 SNP rs1893217 is associated with decreased IL2 signaling in

CD4+ T cells in healthy subjects (32). In type 1 diabetes subjects, decreased IL2

signaling has been shown to affect maintenance of FOXP3 expression in Treg cells

(33). Hence, it is plausible the PTPN2 SNP rs1893217 could alter B cell signaling, as it

has been shown to do in T cells, or impair development of Treg cells. The absence of

Treg cells in the periphery has been shown to lead to the accumulation of autoreactive

B cells (34) and loss of B cell anergy (35). Consistent with this, studies in our lab have

demonstrated that loss of IBC BND cells in FDRs is correlated with decreased frequency

of CD4+CD25hiCD127lo Treg cells in the peripheral blood (Supplemental figure 2).

IKZF3 is a member of the Ikaros family of zincfinger proteins that regulate B cell

proliferation and differentiation. Though not well studied in the context of type 1

diabetes, B cells in IKZF3deficient mice have an activated phenotype (36), and the

mice spontaneously develop human systemic lupus erythematosus (SLE)like features, Diabetes Page 14 of 63

including production of antinuclear antibodies and glomerulonephritis (37). Hence, loss of IBC BND cells in individuals carrying the type 1 diabetes riskassociated IKZF3 SNP could be due to changes in activation threshold caused by the polymorphism.

Taken together our results indicate that loss of anergy in IBCs is associated with high risk HLA and nonHLA type 1 diabetes genotypes. These risk alleles could act in B cell intrinsic fashion to undermine B cell anergy, thereby enabling autoantigen presentation and consequently, development of type 1 diabetes. Genetic risk could also act in B cell extrinsic fashion by allowing more insulinreactive T cells to enter the periphery, increasing T cell help. Finally, risk alleles may promote loss of Treg cells.

Studies are underway to explore these possibilities, including experiments in reductionist models of the effect of the individual risk alleles on B cell anergy in a fixed genetic background. In addition, we are undertaking longitudinal studies to determine whether disappearance of anergic cells from peripheral blood of FDRs is predictive of later development of autoantibodies and disease.

Page 15 of 63 Diabetes

ACKNOWLEDGEMENTS

This work was supported by grants from the National Institutes of Health

(DP3DK110845, R21AI124488, R01AI124487, R01DK096492, P01AI42288,

F30OD021477). None of the authors have confict of interest related to the manuscript

and its findings. Dr. John Cambier is the guarantor of this work and, as such, had full

access to all the data in the study and takes responsibility for the integrity of the data

and the accuracy of the data analysis.

Author contributions: J.C.C. and P.A.G. designed the research; J.C.C., P.A.G., C.E.M,

and M.A.A. provided funding, reviewed and edited the manuscript; C.E.M. and M.A.A.

designed and funded the genotyping SNP kit. M.J.S. performed experiments for Figures

13 and analyzed the data; M.R. was the study coordinator; C.W. assisted in nonHLA

genotyping; M.J.S. and J.C.C. wrote the manuscript.

Diabetes Page 16 of 63

References

1. Fiorina P, Vergani A, Dada S, Jurewicz M, Wong M, Law K, Wu E, Tian Z, Abdi R, Guleria I, Rodig S, Dunussi-Joannopoulos K, Bluestone J, Sayegh MH: Targeting CD22 reprograms B-cells and reverses autoimmune diabetes. Diabetes 2008;57:3013-3024 2. Kleffel S, Vergani A, Tezza S, Ben Nasr M, Niewczas MA, Wong S, Bassi R, D'Addio F, Schatton T, Abdi R, Atkinson M, Sayegh MH, Wen L, Wasserfall CH, O'Connor KC, Fiorina P: Interleukin- 10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens. Diabetes 2015;64:158-171 3. Bluestone JA, Herold K, Eisenbarth G: Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010;464:1293-1300 4. Brodie GM, Wallberg M, Santamaria P, Wong FS, Green EA: B-cells promote intra-islet CD8+ cytotoxic T-cell survival to enhance type 1 diabetes. Diabetes 2008;57:909-917 5. Marino E, Tan B, Binge L, Mackay CR, Grey ST: B-cell cross-presentation of autologous antigen precipitates diabetes. Diabetes 2012;61:2893-2905 6. Orban T, Sosenko JM, Cuthbertson D, Krischer JP, Skyler JS, Jackson R, Yu L, Palmer JP, Schatz D, Eisenbarth G: Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2009;32:2269-2274 7. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC: Predominant autoantibody production by early human B cell precursors. Science 2003;301:1374-1377 8. Gay D, Saunders T, Camper S, Weigert M: Receptor editing: an approach by autoreactive B cells to escape tolerance. The Journal of experimental medicine 1993;177:999-1008 9. Halverson R, Torres RM, Pelanda R: Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol 2004;5:645-650 10. O'Neill SK, Getahun A, Gauld SB, Merrell KT, Tamir I, Smith MJ, Dal Porto JM, Li QZ, Cambier JC: Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase- mediated inhibitory signaling cascade required for B cell anergy. Immunity 2011;35:746-756 11. Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD, Linsley PS, Howard M, Goodnow CC: Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. The Journal of experimental medicine 1994;179:425- 438 12. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K, et al.: Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 1988;334:676-682 13. Gauld SB, Benschop RJ, Merrell KT, Cambier JC: Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat Immunol 2005;6:1160-1167 14. Getahun A, Beavers NA, Larson SR, Shlomchik MJ, Cambier JC: Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. The Journal of experimental medicine 2016;213:751-769 15. Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC: Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy. Immunity 2009;31:749-760 Page 17 of 63 Diabetes

16. Smith MJ, Packard TA, O'Neill SK, Henry Dunand CJ, Huang M, Fitzgerald-Miller L, Stowell D, Hinman RM, Wilson PC, Gottlieb PA, Cambier JC: Loss of anergic B cells in prediabetic and new- onset type 1 diabetic patients. Diabetes 2015;64:1703-1712 17. Steck AK, Zhang W, Bugawan TL, Barriga KJ, Blair A, Erlich HA, Eisenbarth GS, Norris JM, Rewers MJ: Do non-HLA genes influence development of persistent islet autoimmunity and type 1 diabetes in children with high-risk HLA-DR,DQ genotypes? Diabetes 2009;58:1028-1033 18. Mychaleckyj JC, Noble JA, Moonsamy PV, Carlson JA, Varney MD, Post J, Helmberg W, Pierce JJ, Bonella P, Fear AL, Lavant E, Louey A, Boyle S, Lane JA, Sali P, Kim S, Rappner R, Williams DT, Perdue LH, Reboussin DM, Tait BD, Akolkar B, Hilner JE, Steffes MW, Erlich HA: HLA genotyping in the international Type 1 Diabetes Genetics Consortium. Clin Trials 2010;7:S75-87 19. Smith MJ, Packard TA, O'Neill SK, Hinman RM, Rihanek M, Gottlieb PA, Cambier JC: Detection and Enrichment of Rare Antigen-specific B Cells for Analysis of Phenotype and Function. J Vis Exp 2017; 20. Pugliese A, Gianani R, Moromisato R, Awdeh ZL, Alper CA, Erlich HA, Jackson RA, Eisenbarth GS: HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 1995;44:608-613 21. Lambert AP, Gillespie KM, Thomson G, Cordell HJ, Todd JA, Gale EA, Bingley PJ: Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. The Journal of clinical endocrinology and metabolism 2004;89:4037-4043 22. Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, Mychaleckyj JC, Todd JA, Bonella P, Fear AL, Lavant E, Louey A, Moonsamy P: HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008;57:1084-1092 23. Schenker M, Hummel M, Ferber K, Walter M, Keller E, Albert ED, Janka HU, Kastendiek C, Sorger M, Louwen F, Ziegler AG: Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: the German BABYDIAB study. Diabetologia 1999;42:671-677 24. Kulmala P, Savola K, Reijonen H, Veijola R, Vahasalo P, Karjalainen J, Tuomilehto-Wolf E, Ilonen J, Tuomilehto J, Akerblom HK, Knip M: Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group. Diabetes 2000;49:48-58 25. Todd JA, Bell JI, McDevitt HO: HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987;329:599-604 26. Horn GT, Bugawan TL, Long CM, Erlich HA: Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Natl Acad Sci U S A 1988;85:6012-6016 27. Leete P, Willcox A, Krogvold L, Dahl-Jorgensen K, Foulis AK, Richardson SJ, Morgan NG: Differential Insulitic Profiles Determine the Extent of beta-Cell Destruction and the Age at Onset of Type 1 Diabetes. Diabetes 2016;65:1362-1369 28. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C: Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature genetics 1997;15:289-292 Diabetes Page 18 of 63

29. Lempainen J, Harkonen T, Laine A, Knip M, Ilonen J: Associations of polymorphisms in non- HLA loci with autoantibodies at the diagnosis of type 1 diabetes: INS and IKZF4 associate with insulin autoantibodies. Pediatric diabetes 2013;14:490-496 30. Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ: The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Current biology : CB 2002;12:446-453 31. Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet C, Galic S, Tremblay ML, Russell SM, Godfrey DI, Tiganis T: T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. The Journal of clinical investigation 2011;121:4758-4774 32. Long SA, Cerosaletti K, Wan JY, Ho JC, Tatum M, Wei S, Shilling HG, Buckner JH: An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells. Genes Immun 2011;12:116-125 33. Long SA, Cerosaletti K, Bollyky PL, Tatum M, Shilling H, Zhang S, Zhang ZY, Pihoker C, Sanda S, Greenbaum C, Buckner JH: Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes 2010;59:407-415 34. Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J, Mayer L, Cancrini C, Passerini L, Bacchetta R, Ochs HD, Torgerson TR, Meffre E: Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood 2013;121:1595-1603 35. Leonardo SM, De Santis JL, Malherbe LP, Gauld SB: Cutting edge: in the absence of regulatory T cells, a unique Th cell population expands and leads to a loss of B cell anergy. Journal of immunology 2012;188:5223-5226 36. Wang JH, Avitahl N, Cariappa A, Friedrich C, Ikeda T, Renold A, Andrikopoulos K, Liang L, Pillai S, Morgan BA, Georgopoulos K: Aiolos regulates B cell activation and maturation to effector state. Immunity 1998;9:543-553 37. Sun J, Matthias G, Mihatsch MJ, Georgopoulos K, Matthias P: Lack of the transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. Journal of immunology 2003;170:1699-1706

Page 19 of 63 Diabetes

FIGURE LEGENDS

Figure 1. Loss of IBC BND cells in autoantibody positive, recent onset type 1

diabetes, and some first-degree relatives. A. Diagram of the adsorbent used to

identify and enrich for insulinbinding B cells (IBCs). B. Representative gating strategy

from a healthy control to identify anergic (BND) IBCs. Gates for IgM and IgD are drawn

based on CD19 T cells and verified using FMO controls. C. BND cells (as percentage of

CD27 IBC+ B cells) in peripheral blood of firstdegree relatives (FDRs) (n=103),

autoantibody positive (AAb+) (n=18), recent onset type 1 diabetes (R/O T1D) (n=21),

longstanding type 1 diabetes (L/S T1D) (n=21), and healthy controls (H/C) (n=49). (***P

< 0.001, Students t test) D. BND cells (as percentage of CD27 IBC+ B cells) in blood of

FDRs of various age groups.

Figure 2. Loss of IBC BND cells is associated with high risk type 1 diabetes HLA

genotypes. A. Percentage of IBC BND cells in FDRs stratified by HLA genotypes

(n=103). B. Percentage of IBC BND cells in healthy controls (H/C) (n=49) stratified by

HLA genotypes. (*P< 0.05, Students t test) On the xaxis HLA genotypes are listed from

highest to lowest risk for development of type 1 diabetes beginning on the left hand

side.

Figure 3. Loss of IBC BND cells is associated with high risk type 1 diabetes non-

HLA genotypes. Percentage of IBC BND cells in FDRs who carry the risk allele for a

particular SNP or do not. Risk alleles are in bold. Closed circles are FDRs who carry the

nonrisk allele and open circles are FDRs who carry the risk allele. A total of 60 FDRs Diabetes Page 20 of 63

were analyzed for the presence or absence of each risk allele. (*P< 0.05, **P< 0.01,

Students t test) Page 21 of 63 Diabetes A.

anti-A647-MACS bead insulin-biotin

insulin-binding streptavidin-A647 B cell

B.

5 5 5 1.0% 92.2% 10 Naive B cells 10 IBCs 10

104 104 104

103 103 103 T cells 2 2 2 10 10 10 BND 0 0 0 3.3% 3.5%

0 102 103 104 105 0 102 103 104 105 0 102 103 104 105 CD19 CD27 105 105 1.8% 0.2%

104 104

103 103

102 102

0 0 98% 0% 2 3 4 5 2 3 4 5 CD19 0 10 10 10 10 IgM 0 10 10 10 10 Insulin-binding IgD

C. D. ns *** ns 10 *** 10 ND ND

5 5 % IBC B % IBC B (from FDRs) (from

0 0 Age 0-14 15-24 >24 FDR H/C AAb+ R/O T1D L/S T1D Diabetes Page 22 of 63 A. B. * ** * * 8 ** 10 ND ND 6

4 5

2 (from (from H/Cs) % IBC B % IBC B (from (from FDRs)

0 0

DR4/4 DR4/x DR3/x Other DR4/4 DR4/x DR3/x Other

DR3/4 DQ2/8 DR3/4 DQ2/8 DQ6 protective DQ6 protective Page 23 of 63 Diabetes

PTPN2 PTPN22 (rs1893217) (rs2476601) 15 15 * ND ND 10 10

5 5 % IBC B % IBC B (from FDRs) (from (from FDRs) (from 0 0

G T A/A A/ C/C C/

INS IKZF3 (rs689) (rs2872507) 15 ** 15 * ND ND 10 10

5 5 % IBC B % IBC B (from FDRs) (from (from (from FDRs) 0 0

A A T/T T/ G/G G/ Diabetes Page 24 of 63

Supplemental Table 1

Sample ID BND Gene SymbolNCBI SNP ReferenceCall UC1447 0 ADAD1 rs17388568 A/A ATXN2 rs653178 NOAMP ATXN2L;NPIPL1 UC1715 0 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC2857 0 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2931 0 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2932 0 ADAD1 rs17388568 G/G ATXN2 rs653178 C/C ATXN2L UC2991 0 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC2798 0 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2846 0 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2988 0 ADAD1 rs17388568 G/G ATXN2 rs653178 C/C ATXN2L UC2817 0.142 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC3031 0.33 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2976 0.39 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC3047 0.5 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2816 0.57 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC3001 0.615 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2882 0.63 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC3049 0.64 ADAD1 rs17388568 UND ATXN2 rs653178 NOAMP ATXN2L UC2800 0.68 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2853 0.75 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2795 0.77 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2892 0.91 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC3050 1 ADAD1 rs17388568 A/A ATXN2 rs653178 C/T ATXN2L UC2906 1.01 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC2910 1.02 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L UC2845 1.23 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L UC2844 1.43 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2727 1.47 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC3039 1.53 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L UC2914 1.66 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2748 1.73 ADAD1 rs17388568 G/G ATXN2 rs653178 C/C ATXN2L UC1422 1.92 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L;NPIPL1 UC2897 1.92 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2894 2 ADAD1 rs17388568 A/A ATXN2 rs653178 C/T ATXN2L UC2916 2 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2855 2.13 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC1395 2.13 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC3009 2.26 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC1475 2.61 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L;NPIPL1 UC2962 2.62 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2918 2.63 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L UC2905 2.63 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2915 2.68 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC1650 2.76 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L;NPIPL1 UC3078 2.78 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L Page 25 of 63 Diabetes

UC1449 2.88 ADAD1 rs17388568 A/A ATXN2 rs653178 C/C ATXN2L;NPIPL1 UC3067 2.93 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L UC2903 2.98 ADAD1 rs17388568 A/G ATXN2 rs653178 T/T ATXN2L UC2373 2.99 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC3076 3.24 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2880 3.26 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2960 3.41 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2617 3.51 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L;NPIPL1 UC2747 4.26 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC2679 4.31 ADAD1 rs17388568 G/G ATXN2 rs653178 C/C ATXN2L;NPIPL1 UC2856 4.53 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC2719 5.4 ADAD1 rs17388568 G/G ATXN2 rs653178 NOAMP ATXN2L;NPIPL1 UC2698 5.64 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC2697 6.08 ADAD1 rs17388568 A/A ATXN2 rs653178 UND ATXN2L;NPIPL1 UC2893 6.08 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC2815 6.24 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L UC3034 6.25 ADAD1 rs17388568 G/G ATXN2 rs653178 T/T ATXN2L UC3068 6.25 ADAD1 rs17388568 A/G ATXN2 rs653178 C/T ATXN2L UC2440 6.3 ADAD1 rs17388568 G/G ATXN2 rs653178 C/T ATXN2L;NPIPL1 UC2955 10.4 ADAD1 rs17388568 A/G ATXN2 rs653178 C/C ATXN2L Diabetes Page 26 of 63

rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527UND C1QTNF6 rs8049439 T/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/C BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527G/G C1QTNF6 rs8049439 C/C BACH2 rs10806425A/C BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425NOAMP BACH2 rs11755527NOAMP C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527G/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 C/C BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/C BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 T/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425UND BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/C BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 UND BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527NOAMP C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 Page 27 of 63 Diabetes

rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527NOAMP C1QTNF6 rs8049439 C/T BACH2 rs10806425A/A BACH2 rs11755527G/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/A BACH2 rs11755527NOAMP C1QTNF6 rs8049439 C/C BACH2 rs10806425C/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/C BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 C/C BACH2 rs10806425C/C BACH2 rs11755527NOAMP C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/C BACH2 rs10806425C/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425A/A BACH2 rs11755527UND C1QTNF6 rs8049439 T/T BACH2 rs10806425A/C BACH2 rs11755527NOAMP C1QTNF6 rs8049439 T/T BACH2 rs10806425NOAMP BACH2 rs11755527UND C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/C BACH2 rs10806425A/A BACH2 rs11755527C/G C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/C C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 rs8049439 T/T BACH2 rs10806425C/C BACH2 rs11755527NOAMP C1QTNF6 rs8049439 C/T BACH2 rs10806425A/C BACH2 rs11755527C/G C1QTNF6 Diabetes Page 28 of 63

rs229527 NOAMP C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 NOAMP CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 G/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 G/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 NOAMP C1QTNF6 rs229541 NOAMP CCR2 CCR3 rs11711054CCR5 NOAMP CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 Page 29 of 63 Diabetes

rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 NOAMP CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 UND CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/A C1QTNF6 rs229541 A/A CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 UND CCR2 CCR3 rs11711054CCR5 NOAMP CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 NOAMP C1QTNF6 rs229541 NOAMP CCR2 CCR3 rs11711054CCR5 UND CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 UND CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 A/C C1QTNF6 rs229541 A/G CCR2 CCR3 rs11711054CCR5 A/G CCR7;SMARCE1 rs229527 C/C C1QTNF6 rs229541 G/G CCR2 CCR3 rs11711054CCR5 A/A CCR7;SMARCE1 Diabetes Page 30 of 63

rs7221109 NOAMP CD226 rs763361 T/T CLN3 rs151181 C/C CTLA4 rs7221109 NOAMP CD226 rs763361 T/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 C/C CTLA4 rs7221109 C/C CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/C CTLA4 rs7221109 C/T CD226 rs763361 T/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 T/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 T/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 NOAMP CD226 rs763361 NOAMP CLN3 rs151181 NOAMP CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/C CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/C CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 T/T CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 C/C CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 UND CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 T/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 T/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 T/T CLN3 rs151181 T/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 Page 31 of 63 Diabetes

rs7221109 T/T CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/C CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/C CTLA4 rs7221109 T/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/C CTLA4 rs7221109 C/C CD226 rs763361 C/C CLN3 rs151181 T/T CTLA4 rs7221109 T/T CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 NOAMP CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 NOAMP CD226 rs763361 NOAMP CLN3 rs151181 NOAMP CTLA4 rs7221109 C/C CD226 rs763361 T/T CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 T/T CLN3 rs151181 C/C CTLA4 rs7221109 C/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 rs7221109 C/C CD226 rs763361 C/T CLN3 rs151181 C/T CTLA4 rs7221109 C/T CD226 rs763361 C/T CLN3 rs151181 T/T CTLA4 rs7221109 T/T CD226 rs763361 C/C CLN3 rs151181 C/T CTLA4 Diabetes Page 32 of 63

rs3087243 NOAMP CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 UND CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/G CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 NOAMP CTRB2;CTRB1rs7202877 NOAMP CTSH rs3825932 NOAMP CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 UND CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 T/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 T/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 Page 33 of 63 Diabetes

rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 UND CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 T/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/C CYP27B1 rs3087243 NOAMP CTRB2;CTRB1rs7202877 NOAMP CTSH rs3825932 NOAMP CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 T/T CYP27B1 rs3087243 A/A CTRB2;CTRB1rs7202877 G/T CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 UND CTSH rs3825932 C/T CYP27B1 rs3087243 G/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/T CYP27B1 rs3087243 A/G CTRB2;CTRB1rs7202877 T/T CTSH rs3825932 C/C CYP27B1 Diabetes Page 34 of 63

rs10877012UND GAB3 rs2664170 A/A GLIS3 rs1574285 NOAMP GSDMB rs10877012T/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012T/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012T/T GAB3 rs2664170 G/G GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012T/T GAB3 rs2664170 A/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 G/G GSDMB rs10877012NOAMP GAB3 rs2664170 NOAMP GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012NOAMP GAB3 rs2664170 A/G GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 UND GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012T/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 G/G GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 G/T GSDMB rs10877012T/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 G/G GLIS3 rs1574285 G/G GSDMB Page 35 of 63 Diabetes

rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012T/T GAB3 rs2664170 A/G GLIS3 rs1574285 NOAMP GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 G/G GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/G GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 NOAMP GSDMB rs10877012T/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/G GSDMB rs10877012G/G GAB3 rs2664170 G/G GLIS3 rs1574285 G/T GSDMB rs10877012G/G GAB3 rs2664170 A/G GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012NOAMP GAB3 rs2664170 NOAMP GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 G/G GLIS3 rs1574285 T/T GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB rs10877012G/G GAB3 rs2664170 A/A GLIS3 rs1574285 NOAMP GSDMB rs10877012G/T GAB3 rs2664170 A/A GLIS3 rs1574285 G/T GSDMB Diabetes Page 36 of 63

rs2290400 C/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 T/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 C/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 T/T IL10 rs3024505 A/G IL18RAP rs2290400 C/C IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 T/T IL10 rs3024505 A/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 NOAMP IL10 rs3024505 G/G IL18RAP rs2290400 NOAMP IFIH1 rs1990760 NOAMP IL10 rs3024505 NOAMP IL18RAP rs2290400 T/T IFIH1 rs1990760 T/T IL10 rs3024505 A/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 NOAMP IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 UND IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 A/A IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP Page 37 of 63 Diabetes

rs2290400 C/T IFIH1 rs1990760 NOAMP IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 T/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 T/T IL10 rs3024505 A/A IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/C IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 UND IL10 rs3024505 A/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 T/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 NOAMP IFIH1 rs1990760 NOAMP IL10 rs3024505 NOAMP IL18RAP rs2290400 C/C IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 UND IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 T/T IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 A/G IL18RAP rs2290400 T/T IFIH1 rs1990760 C/C IL10 rs3024505 G/G IL18RAP rs2290400 C/T IFIH1 rs1990760 C/T IL10 rs3024505 G/G IL18RAP Diabetes Page 38 of 63

rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 C/C IL2 rs2069762 C/C IL2 rs2069763 G/G IL2RA rs917997 UND IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/G IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 NOAMP IL2 rs2069762 NOAMP IL2 rs2069763 NOAMP IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/G IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 T/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 T/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 C/C IL2 rs2069763 G/G IL2RA rs917997 T/T IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 NOAMP IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 T/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA Page 39 of 63 Diabetes

rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 T/T IL2RA rs917997 UND IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 T/T IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/G IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 UND IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 UND IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/G IL2RA rs917997 UND IL2 rs2069762 C/C IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 NOAMP IL2 rs2069762 UND IL2 rs2069763 UND IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA rs917997 C/C IL2 rs2069762 C/A IL2 rs2069763 G/T IL2RA rs917997 C/T IL2 rs2069762 C/A IL2 rs2069763 G/G IL2RA rs917997 C/T IL2 rs2069762 A/A IL2 rs2069763 G/T IL2RA Diabetes Page 40 of 63

rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495C/C IL2RA rs2104286 C/C IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495NOAMP IL2RA rs2104286 NOAMP IL2RB rs3218253 NOAMP INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/A INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 UND INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH Page 41 of 63 Diabetes

rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/A INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/C IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/C IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 UND IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/C IL2RA rs2104286 C/C IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 C/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/A INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 A/G INS;INS-IGF2;TH rs12722495T/T IL2RA rs2104286 T/T IL2RB rs3218253 G/G INS;INS-IGF2;TH Diabetes Page 42 of 63

rs689 A/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/A KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/A KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 NOAMP KIAA1109 rs4505848 NOAMP MAMSTR;FUT2rs602662 NOAMP MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/A KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP Page 43 of 63 Diabetes

rs689 T/T KIAA1109 rs4505848 G/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/A MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 NOAMP KIAA1109 rs4505848 NOAMP MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 A/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 A/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/A MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP rs689 T/T KIAA1109 rs4505848 A/G MAMSTR;FUT2rs602662 G/G MIR4772;IL18RAP Diabetes Page 44 of 63

rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 NOAMP mt ATP6 rs3135028 NOAMP mt TRNC rs199794187NOAMP mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 G/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 G/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 G/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 G/G mt ATP6 rs3135028 UND mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 a/a mt TRNC rs199794187A/A mt-ND2 Page 45 of 63 Diabetes

rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 G/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 NOAMP mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 NOAMP mt ATP6 rs3135028 UND mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/A mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 rs2058660 A/G mt ATP6 rs3135028 G/G mt TRNC rs199794187A/A mt-ND2 Diabetes Page 46 of 63

rs28357984C/C NUPR1;IL27rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984NOAMP NUPR1 rs4788084 NOAMP PTPN2 rs1893217 NOAMP PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1;IL27rs4788084 T/T PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 NOAMP PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 NOAMP PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 Page 47 of 63 Diabetes

rs28357984C/C NUPR1;IL27rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/G PTPN2 rs28357984NOAMP NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/G PTPN2 rs28357984C/C NUPR1 rs4788084 T/T PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1;IL27rs4788084 C/C PTPN2 rs1893217 A/A PTPN2 rs28357984C/C NUPR1 rs4788084 T/C PTPN2 rs1893217 A/A PTPN2 Diabetes Page 48 of 63

rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 A/A PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 A/A PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 NOAMP PTPN22 rs56048322NOAMP SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322UND SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 Page 49 of 63 Diabetes

rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 A/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 NOAMP PTPN22 rs56048322NOAMP SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 T/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/C PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 NOAMP PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 rs478582 C/T PTPN22 rs2476601 G/G PTPN22 rs56048322C/C SH2B3;ATXN2 Diabetes Page 50 of 63

rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 NOAMP STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 G/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/A STAT4 rs3184504 NOAMP SIRPG;SIRPB1rs2281808 NOAMP STAT4 rs6752770 NOAMP STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 G/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/A STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 NOAMP STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/G STAT4 Page 51 of 63 Diabetes

rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 UND SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 T/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 2.98 SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 NOAMP STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 NOAMP STAT4 rs6752770 UND STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 UND STAT4 rs3184504 C/C SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/G STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/C STAT4 rs6752770 A/A STAT4 rs3184504 C/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 rs3184504 T/T SIRPG;SIRPB1rs2281808 C/T STAT4 rs6752770 A/A STAT4 Diabetes Page 52 of 63

rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/C TCF7L2 rs7574865 NOAMP STAT4 rs7582694 NOAMP TAGAP rs1738074 NOAMP TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 UND STAT4 rs7582694 C/C TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 T/T STAT4 rs7582694 C/C TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 Page 53 of 63 Diabetes

rs7574865 UND STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 UND TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/C TCF7L2 rs7574865 UND STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 NOAMP TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 NOAMP STAT4 rs7582694 NOAMP TAGAP rs1738074 C/C TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 T/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/T STAT4 rs7582694 C/G TAGAP rs1738074 C/T TCF7L2 rs7574865 G/G STAT4 rs7582694 G/G TAGAP rs1738074 C/T TCF7L2 rs7574865 T/T STAT4 rs7582694 C/C TAGAP rs1738074 C/T TCF7L2 Diabetes Page 54 of 63

rs12255372NOAMP TCF7L2 rs7903146 C/C TLR8 rs5979785 NOAMP TLR8 rs12255372T/T TCF7L2 rs7903146 T/T TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372T/T TCF7L2 rs7903146 T/T TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 C/C TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/C TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372NOAMP TCF7L2 rs7903146 NOAMP TLR8 rs5979785 NOAMP TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372T/T TCF7L2 rs7903146 T/T TLR8 rs5979785 C/C TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372T/T TCF7L2 rs7903146 T/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/C TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372T/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 Page 55 of 63 Diabetes

rs12255372G/T TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 C/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/C TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372T/T TCF7L2 rs7903146 T/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372NOAMP TCF7L2 rs7903146 UND TLR8 rs5979785 NOAMP TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/C TLR8 rs5979785 C/C TLR8 rs12255372G/G TCF7L2 rs7903146 C/C TLR8 rs5979785 C/T TLR8 rs12255372G/T TCF7L2 rs7903146 UND TLR8 rs5979785 T/T TLR8 rs12255372G/T TCF7L2 rs7903146 C/T TLR8 rs5979785 T/T TLR8 Diabetes Page 56 of 63

rs936666 T/T TMPRSS3;UBASH3Ars9981624 UND TYK2 rs2304256 NOAMP UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 UND TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 NOAMP TMPRSS3;UBASH3Ars9981624 UND TYK2 rs2304256 NOAMP UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 C/C UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 UND TMPRSS3;UBASH3Ars9981624 UND TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A Page 57 of 63 Diabetes

rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 UND UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 UND TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/C TYK2 rs2304256 A/A UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/A UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 C/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 NOAMP UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 UND TYK2 rs2304256 A/C UBASH3A rs936666 NOAMP TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 NOAMP UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/C TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 C/T TMPRSS3;UBASH3Ars9981624 C/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A rs936666 T/T TMPRSS3;UBASH3Ars9981624 G/G TYK2 rs2304256 A/C UBASH3A Diabetes Page 58 of 63

rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 C/C UBASH3A rs80054410T/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203NOAMP UBASH3A rs1893592 NOAMP UBASH3A rs80054410NOAMP ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203UND UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 NOAMP UBASH3A rs80054410C/T ZPBP2 Page 59 of 63 Diabetes

rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/A UBASH3A rs1893592 A/A UBASH3A rs80054410C/C ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203G/G UBASH3A rs1893592 A/A UBASH3A rs80054410T/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 C/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203G/G UBASH3A rs1893592 C/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203UND UBASH3A rs1893592 NOAMP UBASH3A rs80054410NOAMP ZPBP2;GSDMB;IKZF3 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/C UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203A/G UBASH3A rs1893592 A/A UBASH3A rs80054410C/T ZPBP2 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2;GSDMB;IKZF3 rs11203203G/G UBASH3A rs1893592 A/C UBASH3A rs80054410T/T ZPBP2 Diabetes Page 60 of 63

rs2872507 NOAMP rs2872507 A/G rs2872507 A/A rs2872507 A/G rs2872507 A/A rs2872507 G/G rs2872507 A/G rs2872507 A/G rs2872507 G/G rs2872507 G/G rs2872507 A/G rs2872507 G/G rs2872507 A/A rs2872507 G/G rs2872507 A/A rs2872507 A/G rs2872507 NOAMP rs2872507 G/G rs2872507 A/A rs2872507 G/G rs2872507 G/G rs2872507 A/G rs2872507 A/A rs2872507 A/G rs2872507 A/A rs2872507 G/G rs2872507 G/G rs2872507 G/G rs2872507 G/G rs2872507 G/G rs2872507 G/G rs2872507 A/A rs2872507 A/G rs2872507 G/G rs2872507 A/G rs2872507 A/A rs2872507 G/G rs2872507 A/G rs2872507 A/G rs2872507 A/G rs2872507 G/G rs2872507 A/G rs2872507 G/G rs2872507 A/G Page 61 of 63 Diabetes

rs2872507 A/G rs2872507 A/G rs2872507 G/G rs2872507 NOAMP rs2872507 G/G rs2872507 A/G rs2872507 G/G rs2872507 NOAMP rs2872507 G/G rs2872507 G/G rs2872507 A/G rs2872507 G/G rs2872507 G/G rs2872507 NOAMP rs2872507 A/A rs2872507 G/G rs2872507 G/G rs2872507 UND rs2872507 G/G rs2872507 A/G Diabetes Page 62 of 63

150000 800000

600000 100000 PBMCs PBMCs 7 6 400000

50000 200000 Absolute # of IBC cells / 10 cells / 10 Absolute # of CD19+

0 0

FDR AAb+ FDR AAb+ T1D (L/S) T1D (R/O) T1D (R/O)T1D (L/S)

Healthy Control Healthy Control

* p = 0.03 * p = 0.013 2500

ND 2000

1500 PBMCs 7

1000

500 cells / 10 Absolute # of IBC B 0

FDR AAb+

T1D (R/O)T1D (L/S)

Healthy Control

Supplemental figure 1: Absolute numbers of total B, IBC, and IBC BND cells Page 63 of 63 Diabetes

10

8

6

4 2 2 r =0.373

0

% Treg (of CD4+ cells) CD4+ (of Treg % 0 1 2 3 4 5 % BND

Supplemental figure 2. Decreased frequency of BND cells is associated with decreased frequeny of Treg cells in the peripheral blood of FDRs